After unilateral cerebral damage, a major contributor to overall functional outcome is the development of compensatory behavioral changes involving the ipsilesional, less-affected, body side. While it is often assumed that behavioral compensation is merely an example of learning, this learning may be among the most significant behavioral changes of an animal's adult life and must be accomplished in the presence of major lesion-induced brain changes. Understanding the neural basis for this behavioral change and how it interacts with lesion-induced degenerative events was the focus of the last project period. We determined that skill acquisition in the ipsilesional forelimb in rats is enhanced by unilateral damage to the sensorimotor cortex (SMC), at least in part as a result of a denervation-induced enhancement of learning-induced neuronal structural changes in the motor cortex contralateral to the lesion. We have also recently discovered that behavioral experiences with the less affected forelimb can worsen performance in the impaired forelimb in a manner that cannot be duplicated in intact animals. The focus of the present project is the nature and neural basis of this experience-dependent worsening of function of the impaired limb after unilateral ischemic SMC lesions in adult rats. The central hypothesis of the proposal is that excessive behavioral experience with the less- affected forelimb suppresses neuroplastic processes in remaining regions of infarcted cortex that could otherwise be used to mediate recovery of function in the impaired forelimb. This will be tested using a combination of sensitive behavioral measures and manipulations and rigorous assays of neuronal structural changes and plasticity of movement representations in the peri-infarct cortex. The aims are to test: (1) the contribution of asymmetry and modality of behavioral experience with the less-affected forelimb on function of the impaired limb, (2) the hypothesis that experiences with the less affected forelimb suppress the ability to drive functionally relevant neuronal plasticity in peri-lesion cortex, (3) the dependency of these effects on activity of the contralesional cortex and transcallosal connections, (4) the post-lesion time- dependency of behavioral experiences with the less-affected forelimb and (5) the possibility that these effects can be overcome by a period of early rehabilitative training focused on the impaired limb. The translational relevance of these studies is that asymmetries in behavioral function and interhemispheric interactions are a prominent result of unilateral brain damage. Understanding how they contribute to functional recovery may guide rehabilitation efforts and interventions after unilateral cerebral stroke and other lateralized brain damage.